Von Willebrand's Disease

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Von Willebrand's Disease

In this article

This is the most common hereditary coagulopathy in humans. It can be congenital or acquired. It was described in 1926 by Erik von Willebrand in inhabitants of the Aland Islands in the Sea of Bothnia between Sweden and Finland. It was called 'pseudohemophilia' but later became known as vascular haemophilia.

Pathophysiology

Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF). vWF is a multimeric glycoprotein encoded for by gene map locus 12p13.31.[1]It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions:

It assists in platelet plug formation by attracting circulating platelets to the site of damage.

It binds to coagulation factor VIII preventing its clearance from the plasma.

Epidemiology

Prevalence is as high as 1-2% in the general population on unselected screening.

Worldwide incidence is around 125 per million with between 0.5 and 5 per million being severely affected.

Most patients have mild disease.

It is more common in females.

It is more severe with blood type O.

Presentation

This varies according to the extent of the deficiency:

Bleeding tendency from mucosa - eg, epistaxis, menorrhagia (consider in women with no other obvious cause).

Spontaneous bleeding - eg, internal or joint bleeding (only in the most severe of cases).

Blood clots during childbirth (rare).

Death may occur.

Aetiology

Hereditary - three types (see below).

Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in lymphoproliferative or myeloproliferative disorders and can also be associated with solid tumours, immunological and cardiovascular disorders, and various other conditions - eg, aortic stenosis, Wilms' tumour, hypothyroidism.[2]

Classification of hereditary types

Types of hereditary von Willebrand's disease (vWD)

Type of vWD

Epidemiology - percentage of all cases

Quantitative or qualitative defect

Genetics

Presentation

Type 1

60-80%

Quantitative defect (19-45% of enzyme level present)

Heterozygous for defective gene

Inherited as autosomal dominant (AD)

Normal lifespan

Occasionally easy bruising and/or menorrhagia

Bleeding after dental work, major surgery

Type 2

20-30%

Qualitative defect - multimers abnormal or subgroups absent

Usually AD inheritance

Rarely autosomal recessive (AR)

Bleeding tendency varies

Four subtypes:2A, 2B, 2M, 2N

Type 3

Rare - the most severe form; 1-5% of cases

Quantitative - levels very low or undetectable

Homozygous for defective gene

AR inheritance

No vWF antigen

Low factor VIII

Severe mucosal bleeding

May have haemarthrosis (as in haemophilia)

Platelet type

Rare - fewer than 70 cases described

Functional mutations of vWF receptor on platelet

AD

Subtypes of type 2

Type 2A

Abnormal synthesis or proteolysis of vWF multimers.

Leads to small multimers in circulation; factor VIII still binds as normal.

Type 2B

Spontaneous binding of platelets with rapid clearance of platelets and large vWF multimers.

Mild thrombocytopenia.

Factor VIII binding normal or low normal.

Desmopressin will not help, as it leads to unwanted platelet aggregation.

Type 2M

Low or absent binding to receptor on platelets.

Factor VIII binds as normal.

Type 2N

Autosomal recessive rather than X-linked.

Shows incomplete response to haemophilia A treatment.

Factor VIII levels reduced to around 5%, as vWF has a reduced affinity for factor VIII.

Investigations

The severity of vWD varies and many patients will never be diagnosed, as their disorder may never come to light. In practice - both primary and secondary - the patients with more severe forms of the disorder will present with abnormal bleeding.

Following this, basic blood tests including FBC, clotting screen and liver function should be performed and patients should be referred for a specialist opinion and other more specialised investigations such as plasma levels of vWF. The haematologist will also be able to test for other bleeding disorders which will form part of the differential diagnosis.

Pregnancy and von Willebrand's disease

During pregnancy the level of vWF increases in most women with types 1 and 2 vWD and labour and delivery usually proceed normally. However, patients with type 2B disease may experience haemorrhagic problems. Women with vWD whose vWF does not rise to normal levels during pregnancy need specialist assessment and multidisciplinary team management.[5]

Management

Educate patients as to the bleeding risk. Provide advice regarding drugs that must be avoided such as non-steroidal anti-inflammatory drugs and antiplatelet drugs.

Minor bleeding problems, such as bruising or a brief nosebleed, may not require any specific treatment.

Tranexamic acid is an antifibrinolytic agent. It can be used topically, as a mouthwash, orally or intravenously, as a treatment for minor bleeding or given before surgery, either on its own or as an adjunct to desmopressin or concentrates.

Desmopressin (DDAVP®) works by temporarily increasing factor VIII and vWF levels by releasing endothelial stores. It is given intranasally or parentally.[6]It can be used to treat bleeding complications or prophylactically before surgery. It's ineffective in type 3 vWD as there are no vWF levels to boost. It is not recommended for type 2B vWD as a transient thrombocytopenia may occur and the therapeutic response is usually poor.[5]

Since individual response to desmopressin is unpredictable, all vWD patients should undergo a therapeutic trial of administration to assess their response.[7]

Platelet transfusions may be helpful in some patients with disease refractory to other therapies.

For prophylaxis in major surgery or for treatment of serious bleeding episodes, vWF-containing factor VIII concentrates are the treatment of choice.

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